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Eukaryotic initiation factor 6 is rate-limiting in translation, growth and transformation

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Cell growth and proliferation require coordinated ribosomal biogenesis and translation. Eukaryotic initiation factors (eIFs) control translation at the rate-limiting step of initiation1,2. So far, only two eIFs connect extracellular stimuli to global translation rates3: eIF4E acts in the eIF4F complex and regulates binding of capped messenger RNA to 40S subunits, downstream of growth factors4,5, and eIF2 controls loading of the ternary complex on the 40S subunit and is inhibited on stress stimuli6,7. No eIFs have been found to link extracellular stimuli to the activity of the large 60S ribosomal subunit. eIF6 binds 60S ribosomes precluding ribosome joining in vitro8,9,10. However, studies in yeasts showed that eIF6 is required for ribosome biogenesis rather than translation11,12,13,14. Here we show that mammalian eIF6 is required for efficient initiation of translation, in vivo. eIF6 null embryos are lethal at preimplantation. Heterozygous mice have 50% reduction of eIF6 levels in all tissues, and show reduced mass of hepatic and adipose tissues due to a lower number of cells and to impaired G1/S cell cycle progression. eIF6+/- cells retain sufficient nucleolar eIF6 and normal ribosome biogenesis. The liver of eIF6+/- mice displays an increase of 80S in polysomal profiles, indicating a defect in initiation of translation. Consistently, isolated hepatocytes have impaired insulin-stimulated translation. Heterozygous mouse embryonic fibroblasts recapitulate the organism phenotype and have normal ribosome biogenesis, reduced insulin-stimulated translation, and delayed G1/S phase progression. Furthermore, eIF6+/- cells are resistant to oncogene-induced transformation. Thus, eIF6 is the first eIF associated with the large 60S subunit that regulates translation in response to extracellular signals.

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Figure 1: eIF6 reduction leads to diminished body weight and affects liver growth at the proliferation level.
Figure 2: eIF6 reduction results in 80S complex accumulation and a blunted translational response to insulin.
Figure 3: eIF6 reduction in the cytoplasmic compartment does not affect 60S ribosomal biogenesis.
Figure 4: eIF6 reduction impairs G1/S progression in synchronized cells and causes reduced transformation.

Change history

  • 24 November 2008

    An error was corrected in Fig. 4c on 24 Nov 2008; see PDF for details.


  1. Kapp, L. D. & Lorsch, J. R. The molecular mechanics of eukaryotic translation. Annu. Rev. Biochem. 73, 657–704 (2004)

    CAS  Article  Google Scholar 

  2. Gebauer, F. & Hentze, M. W. Molecular mechanisms of translational control. Nature Rev. Mol. Cell Biol. 5, 827–835 (2004)

    CAS  Article  Google Scholar 

  3. Proud, C. G. Signalling to translation: how signal transduction pathways control the protein synthetic machinery. Biochem. J. 403, 217–234 (2007)

    CAS  Article  Google Scholar 

  4. Sonenberg, N. & Pause, A. Signal transduction. Protein synthesis and oncogenesis meet again. Science 314, 428–429 (2006)

    CAS  Article  Google Scholar 

  5. Mamane, Y., Petroulakis, E., LeBacquer, O. & Sonenberg, N. mTOR, translation initiation and cancer. Oncogene 25, 6416–6422 (2006)

    CAS  Article  Google Scholar 

  6. Holcik, M. & Sonenberg, N. Translational control in stress and apoptosis. Nature Rev. Mol. Cell Biol. 6, 318–327 (2005)

    CAS  Article  Google Scholar 

  7. Wek, R. C., Jiang, H. Y. & Anthony, T. G. Coping with stress: eIF2 kinases and translational control. Biochem. Soc. Trans. 34, 7–11 (2006)

    CAS  Article  Google Scholar 

  8. Russell, D. W. & Spremulli, L. L. Purification and characterization of a ribosome dissociation factor (eukaryotic initiation factor 6) from wheat germ. J. Biol. Chem. 254, 8796–8800 (1979)

    CAS  PubMed  Google Scholar 

  9. Valenzuela, D. M., Chaudhuri, A. & Maitra, U. Eukaryotic ribosomal subunit anti-association activity of calf liver is contained in a single polypeptide chain protein of Mr = 25,500 (eukaryotic initiation factor 6). J. Biol. Chem. 257, 7712–7719 (1982)

    CAS  PubMed  Google Scholar 

  10. Ceci, M. et al. Release of eIF6 (p27BBP) from the 60S subunit allows 80S ribosome assembly. Nature 426, 579–584 (2003)

    ADS  CAS  Article  Google Scholar 

  11. Sanvito, F. et al. The β4 integrin interactor p27(BBP/eIF6) is an essential nuclear matrix protein involved in 60S ribosomal subunit assembly. J. Cell Biol. 144, 823–837 (1999)

    CAS  Article  Google Scholar 

  12. Si, K. & Maitra, U. The Saccharomyces cerevisiae homologue of mammalian translation initiation factor 6 does not function as a translation initiation factor. Mol. Cell. Biol. 19, 1416–1426 (1999)

    CAS  Article  Google Scholar 

  13. Wood, L. C., Ashby, M. N., Grunfeld, C. & Feingold, K. R. Cloning of murine translation initiation factor 6 and functional analysis of the homologous sequence YPR016c in Saccharomyces cerevisiae . J. Biol. Chem. 274, 11653–11659 (1999)

    CAS  Article  Google Scholar 

  14. Basu, U., Si, K., Warner, J. R. & Maitra, U. The Saccharomyces cerevisiae TIF6 gene encoding translation initiation factor 6 is required for 60S ribosomal subunit biogenesis. Mol. Cell. Biol. 21, 1453–1462 (2001)

    CAS  Article  Google Scholar 

  15. Biffo, S. et al. Isolation of a novel β4 integrin-binding protein (p27(BBP)) highly expressed in epithelial cells. J. Biol. Chem. 272, 30314–30321 (1997)

    CAS  Article  Google Scholar 

  16. Clark, R. L. & Hansen, R. J. Insulin stimulates synthesis of soluble proteins in isolated rat hepatocytes. Biochem. J. 190, 615–619 (1980)

    CAS  Article  Google Scholar 

  17. Strezoska, Z., Pestov, D. G. & Lau, L. F. Bop1 is a mouse WD40 repeat nucleolar protein involved in 28S and 5.8S RRNA processing and 60S ribosome biogenesis. Mol. Cell. Biol. 20, 5516–5528 (2000)

    CAS  Article  Google Scholar 

  18. Sanvito, F. et al. Expression of a highly conserved protein, p27BBP, during the progression of human colorectal cancer. Cancer Res. 60, 510–516 (2000)

    CAS  PubMed  Google Scholar 

  19. Harris, M. N. et al. Comparative proteomic analysis of all-trans-retinoic acid treatment reveals systematic posttranscriptional control mechanisms in acute promyelocytic leukemia. Blood 104, 1314–1323 (2004)

    CAS  Article  Google Scholar 

  20. Senger, B. et al. The nucle(ol)ar Tif6p and Efl1p are required for a late cytoplasmic step of ribosome synthesis. Mol. Cell 8, 1363–1373 (2001)

    CAS  Article  Google Scholar 

  21. Menne, T. F. et al. The Shwachman–Bodian–Diamond syndrome protein mediates translational activation of ribosomes in yeast. Nature Genet. 39, 486–495 (2007)

    CAS  Article  Google Scholar 

  22. Volta, V. et al. Sen34p depletion blocks tRNA splicing in vivo and delays rRNA processing. Biochem. Biophys. Res. Commun. 337, 89–94 (2005)

    CAS  Article  Google Scholar 

  23. Chendrimada, T. P. et al. MicroRNA silencing through RISC recruitment of eIF6. Nature 447, 823–828 (2007)

    ADS  CAS  Article  Google Scholar 

  24. Eulalio, A., Huntzinger, E. & Izaurralde, E. GW182 interaction with Argonaute is essential for miRNA-mediated translational repression and mRNA decay. Nature Struct. Mol. Biol. 15, 346–353 (2008)

    CAS  Article  Google Scholar 

  25. Gorrini, C. et al. Fibronectin controls cap-dependent translation through β1 integrin and eukaryotic initiation factors 4 and 2 coordinated pathways. Proc. Natl Acad. Sci. USA 102, 9200–9205 (2005)

    ADS  CAS  Article  Google Scholar 

  26. Zou, X. et al. Cdk4 disruption renders primary mouse cells resistant to oncogenic transformation, leading to Arf/p53-independent senescence. Genes Dev. 16, 2923–2934 (2002)

    CAS  Article  Google Scholar 

  27. Yang, Y. L. et al. BubR1 deficiency results in enhanced activation of MEK and ERKs upon microtubule stresses. Cell Prolif. 40, 397–410 (2007)

    CAS  Article  Google Scholar 

  28. Colombo, E., Marine, J. C., Danovi, D., Falini, B. & Pelicci, P. G. Nucleophosmin regulates the stability and transcriptional activity of p53. Nature Cell Biol. 4, 529–533 (2002)

    CAS  Article  Google Scholar 

  29. Betts, D. H., Barcroft, L. C. & Watson, A. J. Na/K-ATPase-mediated 86Rb+ uptake and asymmetrical trophectoderm localization of alpha1 and alpha3 Na/K-ATPase isoforms during bovine preattachment development. Dev. Biol. 197, 77–92 (1998)

    CAS  Article  Google Scholar 

  30. Serrano, M., Lin, A. W., McCurrach, M. E., Beach, D. & Lowe, S. W. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 88, 593–602 (1997)

    CAS  Article  Google Scholar 

  31. De Palma, M. & Naldini, L. Transduction of a gene expression cassette using advanced generation lentiviral vectors. Methods Enzymol. 346, 514–529 (2002)

    CAS  Article  Google Scholar 

  32. Ceci, M. et al. Release of eIF6 (p27BBP) from the 60S subunit allows 80S ribosome assembly. Nature 426, 579–584 (2003)

    ADS  CAS  Article  Google Scholar 

  33. Rim, J. S., Mynatt, R. L. & Gawronska-Kozak, B. Mesenchymal stem cells from the outer ear: a novel adult stem cell model system for the study of adipogenesis. FASEB J. 19, 1205–1207 (2005)

    CAS  Article  Google Scholar 

  34. Strezoska, Z., Pestov, D. G. & Lau, L. F. Functional inactivation of the mouse nucleolar protein Bop1 inhibits multiple steps in pre-rRNA processing and blocks cell cycle progression. J. Biol. Chem. 277, 29617–29625 (2002)

    CAS  Article  Google Scholar 

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This work was supported by grants AIRC (S.B., P.C.M.), TELETHON GGB05043, CARIPLO 0578 (S.B.) and NIH-RO1 (H.K.). A.B. is supported by grant AICR 05-360. The manuscript has been improved thanks to suggestions from N. Offenhaeuser and A. Boletta. We are indebted to P. G. Pelicci for anti-NPM antibodies, H. Hirai for preliminary soft agar assays, S. Modina for blastocyst preparation, M. Vidali for hepatocytes preparation, M. Malosio for insulin receptor antibodies, S. Gregori for FACS analysis, D. Bartel for reporter constructs, G. Manfioletti for HMGA2 antibodies and F. Loreni for rpS19 antibodies. We acknowledge L. Magri for preliminary experiments, and V. Volta and S. Grosso for suggestions.

Author Contributions V.G., A.M., A.M.B., H.K. and S.B. planned the experiments; V.G., A.M., A.M.B., A.B. and S.B. performed the experiments; all authors analysed the data; and V.G. and S.B. wrote the paper. All authors discussed the results and contributed to the manuscript.

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Correspondence to Stefano Biffo.

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Gandin, V., Miluzio, A., Barbieri, A. et al. Eukaryotic initiation factor 6 is rate-limiting in translation, growth and transformation. Nature 455, 684–688 (2008).

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